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1
Short, John A. L. "Defective interfering particles of parainfluenza virus subtype 5 and interferon induction." Thesis, University of St Andrews, 2015. http://hdl.handle.net/10023/7036.
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The innate immune response is the first line of defence against virus infection. Cells contain a diverse array of pathogen recognition receptors (PRRs) that are able to recognise multiple pathogen associated molecular patterns (PAMPS) that present themselves during virus infection. The RIG-I (Retinoic acid inducible–gene-I) and MDA5 (melanoma differentiation- associated gene 5) PRRs detect specific viral RNA ligands and subsequently induce the expression of the cytokine Interferon-β(IFN-β). IFN-βis secreted, acting on the infected cell and neighbouring uninfected cells to generate an antiviral state that is hostile to virus transcription, replication and dissemination, whilst also orchestrating adaptive immune responses. Given IFN-βs crucial cellular antiviral role, understanding its induction is of great importance to developing future antiviral drugs and vaccine strategies. Using A549 reporter cells in which GFP expression is under the control of the IFN-βpromoter, we show that there is a heterocellular response to parainfluenza virus 5 (PIV5) and infection with other negative sense RNA viruses. Only a limited number of infected cells are responsible for IFN-βinduction. Using PIV5 as a model, this thesis addresses the nature of the PAMPs that are responsible for inducing IFN-βfollowing PIV5 infection. The previous work has shown that PIV5 Defective Interfering particle (DI) rich virus preparations acted as a better inducer of IFN-βcompared to DI poor stocks. DIs are incomplete virus genomes produced during wild-type virus replication as a result of errors in the viral polymerase. To investigate this further, A549 Naïve, MDA5/RIG-I/LGP2 Knock down reporter cells were infected with PIV5 W3 at a low MOI to examine the inverse correlation of NP and GFP of DIs generated during virus replication and not from the initial infection. GFP+ve cells were cell sorted, and using QPCR it was found that cells that have the IFN-βpromoter activated contain large amounts of DIs relative to GFP-ve cells. This data supports the Randall group's findings that DIs generated during errors of wild-type replication by the viral RNA polymerase are the primary PAMPs that induce of IFN-β, as opposed to PAMPs being generated during normal wild-type virus replication.
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Jones, Meleri. "Interfering with interferon : developing a reporter system to study the interaction between hepatitus C viral proteins and the interferon signalling pathway." Thesis, Queen Mary, University of London, 2008. http://qmro.qmul.ac.uk/xmlui/handle/123456789/1530.
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The aim of the project was to investigate the mechanism by which HCV evades therapeutic IFN treatment. This involved the development of novel testing systems and their application to patient samples. Initial experiments focused on flavivirus replicons and novel observations on effects of one of these replicons (dengue virus) on interferon signalling were made. The dengue replicon system was demonstrated to inhibit IFNa signalling by reducing the expression of STAT2, an essential component of the type I IFN signalling pathway. This phenomenom was then further examined in dengue virus infected human cells and again it was observed that the expression of STAT2 was reduced. The mechanism of STAT2 degradation was further explored and STAT2 expression was found to be restored using a proteasomal inhibitor. A second flavivirus replicon system involving BVDV was also developed as a reporter system, again with novel observations. The BVDV replicon system was shown to be sensitive to the antiviral effects of I FNa and was not shown to inhibit the IFNa signalling pathway. The BVDV replicon was tested as a reporter system using a well-known viral inhibitor of I FNa. The viral inhibitor, inhibited the antiviral action of IFNa on the BVDV reporter. Having developed and validated this system, the effects of a small number of patient derived samples were assessed and it was demonstrated that NS5a derived from a patient who failed to respond to IFNa treatment inhibited the effects of IFNa on the BVDV reporter. To increase the senstitivity of the assay the reporter cassette was then changed to a destabilised GFP for use in a FACS based assay.
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Busche, Andreas. "Identifizierung und Charakterisierung von Modulatoren der Interferon-[gamma]-Antwort [Interferon-Gamma-Antwort]." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=96971954X.
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Migliorini, Adriana. "Role of interferon-α and interferon-β in glomerular injury and repair." Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-168014.
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Obwohl die immunstimulatorischen Effekte viraler Nukleinsäursen, wie auch IFN -α und IFN-β, während Virusinfektionen eine wichtige Rolle spielen, ist wenig über ihre Funktion bei viraler Glomerulonephritis, wie beispielsweise HIV Nephropathie, bekannt. Virusinfektionen aktivieren, vor allem mittels IFN-α und IFN-β Produktion eine systemische antivirale Immunantwort. Es wurde gezeigt, dass diese inflammatorischen Zytokine einen pleiotropen immunmodulatorischen Effekt auf renale Mesangialzellen ausüben, was direkt zu glomerulären Krankheiten führt. Aber es ist bisher nicht bekannt, ob die viralen Nukleinsäuren und Typ I IFN einen Effekt auf die glomerulären Epithelzellen haben. (z.B. Podozyten und PECs). Um den Effekt von Nukleinsäuren auf Podozyten und PECs zu erforschen, stimulierten wir diese Zellen mit synthetischen dsDNA-(poly-dAdT) Komplexen mit lipofectamine, um eine virale Infektion zu imitieren. Wir haben herausgefunden, dass dsDNA stetig viele IFN-stimulierte Gene in Podozyten und PECs induziert. Desweitern haben wir herausgefunden, dass dsDNA die PECs Proliferation mindert und die CD24+/CD133+PECs Differenzierung zu ausgereiften Podozyten inhibiert. Um unsere Hypothese, dass deis aufgrund von der Sekretion von IFN-α und IFN-β passiert ist, zu bestätigen, haben wir den Effekt von diesen anitviralen Zytokinen auf PECs- und Podozyten-Homöostase etabliert. Wir haben herausgefunden, dass beide IFNs stetig Podozyten und PECs dazu anregen, stetig mehrere IFN-stimulierte Gene zu exprimieren. Trotzdem hat nur IFN-β das Podozytensterben induziert und die Permeabilität der Podozyten-Monolayer erhöht.
In der Adriamycin-induzierter Nephropathie bei SCID Mäusen haben Injektionen mit IFN-α oder IFN-β die Proteinurie, den Makrophagen Influx und die Glomerulosklerose verstärkt. Trotzdem induziert nur IFN-β das mitotische Podozytensterben (katastrophale Mitose), welches zu einer reduzierten Podozytenanzahl führt. Wir haben führt, dass IFN-α einen Zellzyklusarrest in-vivo bei PECs induziert, der zur glomerulären Schädigung führt. Balb/c Mäuse, die Adriamycin gespritzt bekommen haben und täglich mit IFN-α und IFN-β behandelt wurden zeigten einen aggravierten Phänotyp mit vermehrter Proteinurie. Im Gegensatz zu dem, was an Studien in SCID Mausen gezeigt wurde, war der Effekt auf die Proteinurie nach IFN-α Behandlung prominenter bei Balb/c Mäusen, verglichen mit IFN-β. Deshalb haben Typ I IFNs einen deutlichen Effekt auf Podozyten und Parietalzellen. Zusammen fördern die Typ I IFNs die Glomerulosklerose durch verstärkten Untergang der Podozyten sowie durch Unterdrückung ihrer Regeneration aus Vorläuferzellen.
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Bazzigher, Luigi G. "Interferon-induced Mx proteins /." Zürich, 1992. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=9650.
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Hosana, Barreto de Oliveira Francisca. "Interferon gama versus asma." Universidade Federal de Pernambuco, 2004. https://repositorio.ufpe.br/handle/123456789/9728.
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Previous issue date: 2004Objetivo: Revisar a literatura científica acerca do papel do interferon gama (IFN-y) na doença atópica, especificamente asma. Métodos: Pesquisados dados do Medline e Lilacs nos últimos 10 anos. Resultados: Vários autores discutem a importância da relação entre a secreção de IFN-y e o componente atópico per se, por outro lado é questionado se esta citocina tem relação direta com a doença asmática, independente do estado atópico. Foi verificada a existência de várias pesquisas relacionando asma e IFN-y; entretanto, os resultados destas pesquisas se apresentam controversos. Conclusão: Ainda não se chegou a uma conclusão definitiva do verdadeiro mecanismo de atuação desempenhado pelo IFN-y na doença asmática, é indiscutível a importância de novas pesquisas esclarecedoras sobre este assunto
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Barbulescu, Karina. "Transkriptionelle Regulation des humanen Interferon-[gamma]-Promotors [Interferon-gamma-Promotors] in T-Lymphocyten." [S.l.] : [s.n.], 1999. http://deposit.ddb.de/cgi-bin/dokserv?idn=959887458.
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Carlton-Smith, Charles. "Impact of interferon β and interferon stimulated gene induction on Bunyamwera virus replication." Thesis, University of St Andrews, 2012. http://hdl.handle.net/10023/3179.
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The first line of defence against viral infection is the interferon (IFN) response, which must be overcome by a virus for successful replication. Pattern recognition receptors detect virus which triggers induction of IFNβ. Secreted IFNβ stimulates the JAK/STAT signal transduction pathway and the upregulation of IFN stimulated genes (ISGs) culminating with expression of hundreds of antiviral proteins. Bunyamwera virus (BUNV) is the prototype virus for the genus Orthobunyavirus and the family Bunyaviridae. BUNV is a trisegmented single stranded negative sense RNA virus whose genome comprises the Large (L), Medium (M) and Small (S) RNA segments. The L segment encodes the RNA polymerase, the M segment the two glycoproteins Gn and Gc and a non-structural protein NSm, and the S segment the nucleoprotein and a non-structural protein NSs in overlapping reading frames. The NSs protein interferes with RNA polymerase II mediated transcription thereby inhibiting cellular mRNA production, including IFN mRNA, and hence it is the primary IFN antagonist. A recombinant virus, rBUNdelNSs, that is unable to express the NSs protein, does not inhibit cellular transcription and is thus a strong IFN inducer. The aim of this thesis was to understand how IFN inhibits BUNV replication. Cells stimulated into the antiviral state by IFN treatment were protected against BUNV infection but addition of IFN 6 hours (or later) post infection had little effect on the replication cycle. However, addition of IFN immediately following infection conferred restriction on BUNV replication by initially increasing viral protein synthesis and then by blocking translation of positive sense viral RNA. To identify ISGs with anti-BUNV activity, I screened a panel of 26 cell lines that inducibly express individual ISGs. To aid screening, recombinant BUNV that expressed green fluorescent protein (GFP) were employed, including an NSs deletion virus with GFP fused to the Gc, rBUNGceGFPdelNSs, that I created and characterised. By a combination of virus yield assays, Western blotting and fluorescence techniques, three cell lines that inducibly express PKR, viperin or MTAP44 were shown to restrict BUNV replication. More detailed studies revealed PKR to restrict BUNV RNA and protein synthesis, but when PKR was knocked-down in IFN competent A549 cells viral replication was not blocked in cells pre-treated with IFN. Viperin inhibited viral protein synthesis and virally-induced host cell protein synthesis shut-off. Additionally, viral RNA synthesis was restricted by viperin and this was dependent on the CX₃CX₂C motif 1 of viperin. Taken together, these data show that the restriction of BUNV replication mediated by IFN is an accumulated effect of several different ISGs acting on different stages of the viral life cycle.
9
Shearer, M. A. "Monoclonal antibodies to human interferon-#alpha# applied to the study of interferon-receptor interaction." Thesis, Open University, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.379866.
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Burkhart, Margi Anne. "Biological activity and therapeutic applications of intracellular interferon gamma and interferon gamma mimetic peptides." [Gainesville, Fla.] : University of Florida, 2003. http://purl.fcla.edu/fcla/etd/UFE0001180.
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Ellegast, Jana. "Interferon-Induktion durch Triphosphat-RNA." Diss., lmu, 2010. http://nbn-resolving.de/urn:nbn:de:bvb:19-113843.
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Ghislain, Julien Johannes. "Type I interferon signal transduction." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0015/NQ27652.pdf.
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Evans, T. J. "Molecular studies of interferon action." Thesis, University of Cambridge, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.372630.
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Gage, Zoe O. "Interferon, viruses and drug discovery." Thesis, University of St Andrews, 2017. http://hdl.handle.net/10023/10127.
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The interferon (IFN) response is a crucial component of cellular innate immunity, vital for controlling virus infections. Dysregulation of the IFN response however can lead to serious medical conditions including autoimmune disorders. Modulators of IFN induction and signalling could be used to treat these diseases and as tools to further understand the IFN response and viral infections. We have developed cell-based assays to identify modulators of IFN induction and signalling, based on A549 cell lines where a GFP gene is under the control of the IFN-β promoter (A549/pr(IFN-β).GFP) and the ISRE containing MxA promoter (A549/pr(ISRE).GFP) respectively. The assays were optimized, miniaturized and validated as suitable for HTS by achieving Z' Factor scores >0.6. A diversity screen of 15,667 compounds using the IFN induction reporter assay identified 2 hit compounds (StA-IFN-1 and StA-IFN-4) that were validated as specifically inhibiting IFNβ induction. Characterisation of these molecules demonstrated that StA-IFN-4 potently acts at, or upstream, of IRF3 phosphorylation. We successfully expanded this HTS platform to target viral interferon antagonists acting upon IFN-signalling. An additional assay was developed where the A549/pr(ISRE).GFP.RBV-P reporter cell line constitutively expresses the Rabies virus phosphoprotein. A compound inhibiting viral protein function will restore GFP expression. The assay was successfully optimized for HTS and used in an in-house screen. We further expanded this assay by placing the expression of RBV-P under the control of an inducible promoter. This demonstrates a convenient approach for assay development and potentiates the targeting of a variety of viral IFN antagonists for the identification of compounds with the potential to develop a novel class of antiviral drugs.
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Henfrey, Andrew Mark. "Studies on ovine interferon-gamma." Thesis, University of Edinburgh, 1993. http://hdl.handle.net/1842/29798.
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Interferons have been recognized as important mediators of cellular communication for many years. There are two types of interferon: Type I interferons have antiviral functions, but Type II interferon (IFN-g) is more important as an immunomodulating molecule. Type II interferon has effects on cellular MHC class II expression, immunoglobulin class-switching, macrophage activation, cellular proliferation and a number of other functions. The role of IFN-g during in vivo immune responses has not been studied in great detail, but the sheep is an ideal species in which to study these phenomena by using the efferent lymphatic vessel cannulation model. This allows access to cells and tissue fluid for cytokine analysis using antibody and genetic probes for the detection of IFN-g. Bovine IFN-g peptides (amino-terminus, carboxy-terminus and central) were used to generate antibodies in rabbits. None of the anti-peptide sera reacted with denatured ovine or bovine IFN-g, nor neutralized their antiviral effect. Rabbit antibodies to bovine recombinant IFN-g neutralized ovine IFN-g and detected IFN-g in a sandwich ELISA when used in combination with a monoclonal antibody against a human IFN-g carboxy-terminal peptide. The sensitivity of detection was only 125ng/ml, insufficient for use with efferent lymph fluid samples. The expression of MHC class II molecules on cell surfaces is increased by IFN-g on many cell types. This has been used previously to measure biologically active IFN-g concentrations in fluids. Measurement of ovine class II by slot blot was assessed as a method of adapting this to ovine IFN-g measurement, but the technique proved to be too problematic for regular use. The expression of class II on T lymphocytes is influenced by IFN-g in the surrounding fluid. Analysis by FACS of resting ovine T lymphocytes shows them to express class II, a situation different to that in the human.
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Herrington-Symes, A. P. "Protein-protein conjugation using interferon." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1464509/.
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Therapeutic proteins are often potent and have rapid onsets of action. Unfortunately protein-based medicines can be immunogenic and have short half-lives. The circulation half-life of many proteins has been improved by the covalent conjugation of poly(ethylene)glycol (PEG) to the protein. For example, PEGylated interferon-2 (PEGASYS® and PEG-INTRON®) has become a first line treatment for hepatitis C. The aim of this thesis was to examine the possibility of using a homobifunctional PEG reagent to make protein dimers. Our group has developed PEGylation reagents that undergo conjugation by bis-alkylation to selectively conjugate either (i) two cysteine thiols from a native disulfide or (ii) two histidine residues in a polyhistidine tag. It was hypothesised that IFN dimers (IFN-PEG-IFN) could be prepared with higher retained activity than monoPEGylated IFN. It was also hypothesised that a heterodimer of IFN and an antibody fragment (Fab) could be made while retaining the activity of both proteins within the heterodimer. His8IFN-PEG-His8IFN and IFN-PEG-IFN homodimers were prepared by site-selective conjugation to the N-terminal 8-polyhistidine tag and to one of the disulfides of IFN respectively. These homodimer conjugates were characterised in terms of purity and in vitro activity. The in vitro cell based assays were optimised to accurately elucidate the specific activities of the IFN conjugates. The His8IFN-PEG20-His8IFN homodimer was found to retain greater activity than IFN-PEG20-IFN. The increased activity was thought to be due to conjugation to the polyhistidine tag, which is distal from the IFN binding surface. It was also found that IFN-PEG10-IFN homodimer retained greater activity than PEG10-IFN, which could be due to the presence of the second IFN molecule in the IFN-PEG10-IFN homodimer. Two different Fabs were used to prepare the IFN-PEG-Fab heterodimers. Conjugation was conducted at one disulfide of IFN and the accessible interchain disulfide of the Fab. One Fab was derived from a polyclonal antibody to albumin (Fabalb) and the rationale for this heterodimer was that a longer lasting form of IFN could be made (IFN-PEG20-Fabalb). The other Fab was derived from bevacizumab (Fabbeva) to give an IFN-PEG20-Fabbeva heterodimer that could, in principle, display antiangiogenic properties. Both heterodimers were evaluated using antiviral and antiproliferative assays to determine the activity of IFN in the conjugate. The IFN-PEG20-Fabalb conjugate displayed a 10-fold reduction in activity compared to IFN-PEG20-Fabbeva. It was thought that Fabalb underwent competitive binding with components of the media. Interestingly, the IFN-PEG20-Fabbeva heterodimer displayed greater activity than PEG20-IFN and IFN-PEG20-IFN in both the antiviral and antiproliferative assays. The binding properties of Fabbeva were determined by SPR. It was observed that the dissociation rate of IFN-PEG20-Fabbeva was similar to Fabbeva and PEG20-Fabbeva. IFN-PEG20-Fabalb was found to have a similar dissociation rate to Fabalb. However, PEG20-Fabalb was found to have a slower dissociation to both IFN-PEG20-Fabalb and Fabalb, this result requires further investigation but was thought to be due to the sample impurity. The association rates of heterodimers were found to similar to the PEG-Fab conjugates but slower than their native Fabs. This data suggests that the novel IFN-PEG20-Fabbeva and IFN-PEG20-Fabalb heterodimer conjugates have retained their binding affinities to their antigens. Overall, it was shown that a homobifunctional bis-alkylating conjugation reagent (e.g. PEG di(bis)sulfone 4) could be used successfully to prepare dimeric protein conjugates. This work highlighted the importance to ensure the homobifunctional conjugation reagent was pure, especially for the preparation of protein heterodimeric conjugates. To develop this work further, it would be important to investigate three broad areas: i) improving the purity of the starting homobifunctional reagents, ii) evaluate the in vivo efficacy of the resulting protein homo-/hetero-dimers and iii) determine the overall potential for efficient scaling of the process to make the desired protein homo-/hetero-dimers.
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Nobre, Rita Luisa Valentim de Avelar. "Viral interferon antagonists and antiviral drugs /." St Andrews, 2009. http://hdl.handle.net/10023/818.
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Zang, Lei. "Optimization of interferon γ gene delivery/expression system towards realization of interferon γ gene therapy." 京都大学 (Kyoto University), 2011. http://hdl.handle.net/2433/142500.
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Bustillos, Ortiz Alcides Alberto. "Efectos de la depleción de la histona H1 en células de cáncer de mama: proliferación y respuesta a interferón." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/457666.
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La histona H1 se une al nucleosoma, situándose en la base, cerca de los sitios de entrada y salida del DNA, siendo una de sus principales funciones descritas, el mantenimiento de una estructura estable y condensada de la cromatina. Los primeros estudios realizados del rol que desempeña H1 en la regulación transcripcional señalaban que H1 era un represor global de la transcripción. Sin embargo, estudios recientes sugieren que H1 desempeña un papel más dinámico y contribuye a una regulación transcripcional específica de genes. Siete variantes de histonas H1 existen en células somáticas humanas (H1.1 a H1.5 que son expresadas de una manera dependiente de la replicación, mientras que H1.0 y H1X son independientes de la replicación). Uno de los principales debates es si dichas variantes de histonas H1 tienen un rol específico o redundante.
En este trabajo investigamos esto a través de RNAs interferentes inducibles para inhibir de manera individual y por primera vez de manera simultánea las variantes de la histona H1 en células de cáncer de mama T47D.
La inhibición individual de las distintas variantes ocasionó una reducción de la velocidad de crecimiento enc omparación a células parentales. Al inhibir de manera simultánea las variantes H1.2 y H1.4, se observó que la proliferación se ve afectada en mayor medida que al inhibir las variantes H1.2 y H1.4 de manera individual. Debido a que la proliferación celular y adhesión celular son características relacionadas con la tumorogénesis e invasión metastásica, se investigó además los efectos de la depleción de las distintas variantes en la capacidad de formar colonias independientes del anclaje. Nuestros resultados sugieren que la variante H1.2 es esencial para que las células crezcan tanto de manera independiente como dependiente del anclaje, lo que sugiere que al inhibir dicha variante las células posiblemente pierden su capacidad metastásica.
La combinación de la depleción de H1.2 y H1.4 indujo una fuerte respuesta a interferón (IFN), efecto que no se observó en depleciones individuales de variantes de histonas H1. Se verificó que la depleción combinada de H1.2 y H1.4 producía la sobreexpresión y síntesis de interferón. Dicha síntesis de IFN indujo la respuesta a IFN en células T47D y activó la ruta JAK-STAT, principal ruta involucrada en la activación de la transcripción de ISGs. Se verificó mediante la combinación de dos RNA interferentes para las variantes H1.4 y H1.2 en T47D(H1.4/H1.2sh) que la respuesta a interferón ocasionada por el multiH1 shRNA, se reproduce al inhibir tanto a nivel de RNA como de proteína únicamente las variantes H1.2 y H1.4. La inhibición de otras combinaciones que incluyen H1.2 con H1.5, H1.4 con H1.5 y triples combinaciones H1.2/H1.5/H1.3 y H1.4/H1.5/H1.3 produjeron, sólo cuando la depleción de H1.2 estuvo involucrada, la sobreexpresión de ISGs a niveles inferiores a los observados en la depleción mH1sh o en la combinación H1.4/H1.2. En las células en las que no se deplecionó H1.2 no se observó la respuesta a interferón.
Por otra parte, la combinación de la depleción de H1.2 y H1.4(H1.4/H1.2sh) con el tratamiento con IFNβ comercial produjo un efecto sinérgico en la sobreexpresión de ISGs, lo que sugiere que existen otros mecanismos de inducción de los ISGs además de la estimulación por el IFN sintetizado. Análisis con inhibidores y knock downs constitutivos de sensores y adaptadores de la respuesta a IFN nos sugieren que posiblemente al deplecionar H1.2/H1.4 se desencadena la expresión de dsRNA no codificantes posiblemente formados desde retrovirus endógenos o de secuencias repetitivas de heterocromatina, y que dichos ácidos nucleicos son los causantes de la activación de la respuesta inmune antiviral, que ocasiona los efectos observados como son la síntesis de IFN, sobreexpresión de ISGs, defectos en la proliferación.Histone H1 binds to linker DNA contributing to higher-order chromatin compaction. In addition, H1 seems to be actively involved in the regulation of nuclear processes such as gene expression control or DNA damage signaling. Seven linker histone H1 variants exist in human somatic cells (H1.1 to H1.5 being expressed in a replication-dependent manner, whereas H1.0 and H1X are replication-independent), with distinct prevalence depending on the cell-type analyzed and along differentiation. It is not well known whether the different variants have specific or redundant roles. We explored this by inducible shRNA- mediated knock-down of each of the H1 variants in breast cancer cells. Knock-down of each H1 variant alters expression of a different reduced subset of genes and affects cell proliferation in a different extent. Although H1.2 is the only variant essential for cells to grow in anchorage-independent conditions, being the H1 that alters the most the proliferative and metastatic properties of cancer cells. Combined depletion of H1.2 and H1.4 has a strong deleterious effect in the cancer cells examined, and induces a strong interferon (IFN) response with up-regulation of many IFN-stimulated genes (ISGs), which is not seen in individual H1 knock-downs. Although H1 participates to repress ISG promoters, its activation upon H1 KD is mainly generated by the activation of the IFN response through cytosolic nucleic acids receptors, IFN synthesis and JAK-STAT pathway activation. The IFN response may be triggered by the expression of noncoding dsRNAs generated from heterochromatic repeats or endogenous retroviruses upon H1 KD. In conclusion, redundant H1-mediated silencing of heterochromatin is important to maintain cell homeostasis and to avoid an unspecific growth-inhibiting IFN response.
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Muñoz, López Laura. "Improving diagnostic strategies for latent tuberculosis infection in populations at risk for developing active disease." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/461911.
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BACKGROUND
Latent tuberculosis infection (LTBI) management is a crucial component of tuberculosis prevention in high-risk individuals. A global approach including diagnosis and treatment completion ensures good outcomes.T-cell-based interferon-gamma release assays (IGRAs) were first developed a decade ago, at which time they represented a promising alternative to the tuberculin skin test (TST); however, they too are limited by their poor ability to predict future active TB, being only slightly better than TST at best. Since the implementation of IGRAs, several cross-sectional studies showed the comparison of TST and IGRAs results in populations at risk for developing active tuberculosis, with still not enough evidence based on longitudinal cohorts and properly designed clinical trials to date.
HYPOTHESIS
1. In immunosuppressed individuals: The addition of an IGRA test might benefit the diagnostic strategy in order to maximize TST sensitivity.
2. In recently infected individuals (contact tracing studies): Implementing the use of IGRAs could narrow the proportion of preventive therapy in individuals at risk of developing active tuberculosis, without increasing its risk.
OBJETIVES
1. Immunosuppressed individuals:
1.1 To assess whether a comprehensive latent tuberculosis screening and treatment program includind an IGRA can prevent anti-TNF–associated tuberculosis.
1.2. To assess the usefulness of QFT-GIT in predicting the development of active tuberculosis in comparison to the TST in patients undergoing liver transplant and hematopoietic stem cell transplant.
2. Contact tracing studies
2.1 To ascertain whether using IGRA, either in place of TST or to confirm a positive TST, might reduce the number of people considered for preventive treatment, without leading to a significant increase in the risk of subsequent active tuberculosis.
2.2 To determine whether the use of QFT-GIT as a confirmatory test of the TST to target preventive therapy in tuberculosis contacts might reduce the number of individuals receiving treatment without an increased risk of subsequent active tuberculosis, as compared to a TST-based strategy.
METHODS
The clinical studies included in this thesis comprise three longitudinal cohort studies, a systematic review and a clinical trial. The three observational studies are retrospective analyses of prospectively gathered data, recorded as part of the clinical assistance in the Tuberculosis Unit at Bellvitge University Hospital.
The research ethics committee approved them all.
The statistical analyses were made with the SPSS (Statistical Package for the Social Sciences) software (version 17 and 22). The level of significance was fixed at α = 5%, and confidence intervals (CIs) for differences in proportions were estimated using OpenEpi software version 2.3.1.122.
RESULTS
1. Immunosuppressed individuals:
1.1 First, although anti-TNF–associated tuberculosis can be greatly reduced, a certain risk remains during the first year of treatment. Second, the 2-step TST approach for LTBI screening prior to anti-TNF therapy is no longer justified. Third, systematic periodic retesting for LTBI in patients with negative test results prior to anti-TNF therapy is not required.
1.2 The rate of post-transplant TB among QFT- GT-positive patients was both low and comparable to that of the TST in this cohort of liver transplant and Hematopoietic Stem Cell Transplant recipients.
2. Contact tracing studies
In low-incidence settings of TB, using QFT-GIT to confirm positive TST reactors allows a significant reduction of TB infection diagnoses and preventive therapy prescriptions without increasing the risk of active disease.ANTECEDENTES: Desde la implementación de los IGRAs (Interferon Gamma Release Assays) se ha generado poca evidencia científica fundamentada en ensayos clínicos o en el seguimiento longitudinal de cohortes. HIPÓTESIS: 1. La implementación de los IGRAs en el cribado de infección tuberculosa latente (ITL) en pacientes inmunodeprimidos puede mejorar la rentabilidad diagnóstica. 2. Los IGRAs pueden optimizar la selección de pacientes candidatos a recibir tratamiento de ITL en el estudio de contactos (EC), reduciendo su número, sin aumentar el riesgo de tuberculosis activa (TB). OBJETIVOS: 1. Demostrar la eficacia de un protocolo sistemático de prevención de TB que incluye un IGRA en los candidatos a anti-TNF. 2. Calcular los valores predictivos (VP) para el desarrollo de TB de la prueba de la tuberculina (PT) y un IGRA en pacientes candidatos a trasplante hepático (TH) o de progenitores hematopoyéticos (PH). 3. Demostrar que basar la indicación del tratamiento para ITL en el resultado de un IGRA disminuye la proporción de candidatos a tratamiento en comparación con PT, sin que por ello aumente el riesgo de TB. MÉTODOS: La tesis responde a los objetivos mediante un ensayo clínico multicéntrico y tres estudios prospectivos aprobados por el Comité de Ética del Hospital de Bellvitge, así como una revisión sistemática. RESULTADOS: 1. En candidatos a agentes anti-TNF se ha demostrado la eficacia del protocolo sistemático para la prevención de TB. El cese de PT en dos tiempos ha supuesto una disminución significativa en la proporción de diagnósticos y tratamientos de ITL sin aumentar del riesgo de TB ulterior. No es necesario repetir el cribado sistemáticamente tras un resultado negativo inicial. 2. En los candidatos a TH y de PH, el VP positivo para el desarrollo de TB del IGRA ha sido comparable a PT, siendo bajo, y por tanto no útil para predecir el desarrollo de TB. El VP negativo ha sido elevado en ambas pruebas. 3. La estrategia diagnóstica que confirma con un IGRA los resultados positivos de la PT ha demostrado ser no inferior a la estrategia basada únicamente en PT para la prevención de tuberculosis en el EC, permitiendo reducir significativamente el número de candidatos a tratamiento preventivo.
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Hidmark, Åsa. "Induction of type I interferons and viral immunity /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-227-9/.
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Harlin, Olof. "Die Bedeutung von Interferon alpha und Interferon gamma auf den Verlauf der Marekschen Krankheit beim Haushuhn." Diss., lmu, 2003. http://nbn-resolving.de/urn:nbn:de:bvb:19-9116.
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Tanaka, Marcia Hiromi [UNESP]. "Análise dos parâmetros clínicos periodontais e expressão genética de interferons alfa, gama e genes relacionados em indivíduos portadores de Síndrome de Down com doença periodontal." Universidade Estadual Paulista (UNESP), 2010. http://hdl.handle.net/11449/88703.
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tanaka_mh_me_arafo.pdf: 647421 bytes, checksum: 7aca1036f8801f2b3143929ea57d6d5c (MD5)A doença periodontal (DP) em indivíduos com Síndrome de Down (SD) se desenvolve com alta prevalência, precocemente, de modo rápido e generalizado em comparação com indivíduos não-sindrômicos. Foi demonstrado que portadores da SD apresentam resposta imune diminuída em relação aos cromossomicamente normais. O objetivo desta pesquisa foi investigar diferenças nos parâmetros clínicos periodontais e níveis de expressão dos genes Interferon-gama (IFNG), Interferon-gama receptor 1 (IFNGR1), Interferon-gama receptor 2 (IFNGR2), Interferon-alfa (IFNA), Interferon-alfa receptor 1 (IFNAR1), Interferon-alfa receptor 2 (IFNAR2), Janus-quinase 1 (JAK1), Transdutor de sinal e ativador da transcrição 1 (STAT1) e Fator de regulação de interferon 1 (IRF1) em indivíduos com SD que apresentam ou não DP e em indivíduos cromossomicamente normais. Fizeram parte deste estudo 80 indivíduos entre 7 e 57 anos de idade subdivididos em 4 grupos: SD com DP (A); indivíduos com SD sem DP (B); indivíduos não-sindrômicos (Controle) com DP (C) e indivíduos Controle sem DP (D). A expressão gênica foi investigada por meio de quantificação relativa utilizando a técnica da Reação em Cadeia da Polimerase (PCR) em Tempo Real. Para o índice sangramento à sondagem (SS) não houve diferença entre os grupos A e 21 C. A periodontite crônica localizada foi o tipo prevalente tanto entre indivíduos com SD como Controle. Considerando os parâmetros clínicos, não foram encontradas diferenças na periodontite crônica localizada entre os indivíduos com SD e Controle, assim como para a periodontite crônica generalizada. Com relação à análise genética, observou-se que indivíduos dos grupos com SD em relação aos grupos cromossomicamente normais (A+B-C+D) tiveram uma expressão de IFNG semelhante ao observado entre indivíduos do grupo...
Periodontal disease (PD) in individuals with Down Syndrome (DS) has an early, quickly and widespread onset and high prevalence when compared with individuals without the Syndrome. Only poor oral hygiene does not explain the severe periodontal destruction seen in DS patients. It has been shown that DS patients have a weaker immune response than people with normal number of chromosomes. The aim of this study was to investigate differences in periodontal clinical parameters and the expression levels of the genes Interferon-gamma (IFNG), Interferon-gamma receptor 1 (IFNGR1), Interferon-gamma receptor 2 (IFNGR2), interferon-alpha (IFNA), interferon-alpha receptor 1 (IFNAR1), Interferon-alpha receptor 2 (IFNAR2), Janus-kinase 1 (JAK1), Signal transducers and activators of transcription 1 (STAT1) and Interferon regulatory factor 1 (IRF1) in DS patients with and without periodontal disease in comparison with chromossomically normal individuals. A total of 80 individuals aged 7 to 57 years participated in this study and were divided into 4 groups: DS with PD (A); DS without PD (B); individuals without DS (control) with PD (C) and individuals without DS (control) and without PD (D). A quantitative RT-qPCR was used to investigate gene expression. There was no difference between groups A and C regarding the bleeding on probing 25 (BOP) index. The most prevalent type of periodontitis seen in this study was the localized chronic periodontitis, both in individuals with and without DS. Considering the clinical parameters, localized and generalized chronic periodontitis did not differ between individuals with and without DS. Regarding genetic analysis, individuals of the groups with DS in relation to the groups without DS (A+B-C+D) showed an IFNG expression similar to that seen among the individuals of groups control with PD (C-D). However, individuals... (Complete abstract click electronic access below)
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Fenner, Jennifer Eve. "Regulation of Type I interferon responses." Monash University, Centre for Functional Genomics and Human Disease, 2003. http://arrow.monash.edu.au/hdl/1959.1/9437.
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Kamphuis, Elisabeth. "Type I interferon stimulation of lymphocytes." Giessen : VVB Laufersweiler, 2007. http://geb.uni-giessen.de/geb/volltexte/2007/4791/index.html.
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Rodrigues, Ana Mara Lopes. "Interferon, virus vaccines and antiviral drugs /." St Andrews, 2007. http://hdl.handle.net/10023/413.
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Kamphuis, Elisabeth. "Type I interferon stimulation of lymphocytes." Giessen VVB Laufersweiler, 2006. http://d-nb.info/988717891/34.
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Röll, Susanne. "Identifizierung Interferon-regulierter Gene beim Haushuhn." Diss., Ludwig-Maximilians-Universität München, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-160492.
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Typ I Interferon stellt einen essentiellen Teil der angeborenen Immunantwort dar und besitzt antivirale und immunmodulatorische Eigenschaften. Diese Funktionen werden durch die Induktion sogenannter Interferon-regulierter Gene (IRGs) vermittelt, deren Expression in der Zelle nach Bindung von IFN an seinen Rezeptor reguliert wird. Im Rahmen dieser Arbeit gelang es mit Hilfe verschiedener Ansätze erstmals, eine umfassende Anzahl Typ I Interferon-regulierte Gene beim Huhn zu identifizieren. Hierzu wurden umfangreiche Datenbankrecherchen und Transkriptomanalysen von Milz und Lunge sowohl nach Applikation von rekombinanten Hühner Interferon alpha, als auch einer Infektion mit Newcastle Disease Virus, einem starken IFN Induktor, durchgeführt. Etwa 30% der hierbei gefundenen IRGs wurden auch im Säugetier als solche beschrieben (allgemeine IRGs), weitere 1.900 Gene, die im Huhn nach Injektion von rekombinanten Hühner Interferon alpha exprimiert wurden sind jedoch beim Säuger in dieser Form nicht bekannt (neu identifizierte IRGs).
Die eingehende Charakterisierung der Hühner-IRGs zeigte, dass „neu identifizierte“ und „allgemeine IRGs“ an ähnlichen immunrelevanten Prozessen und Signalwegen beteiligt waren, wie der Komplement Kaskade, der TLR Signalkaskade und Zytokin-Interaktionen. Auch durch Netzwerkanalysen konnte gezeigt werden, dass die Expression von „allgemeinen“ und „neu identifizierten IRGs“ in engem Zusammenhang miteinander steht. Durch die Untersuchung von verschiedenen Zeitpunkten konnte nachgewiesen werden, dass manche der im Huhn identifizierten IRGs in Milz und Lunge nur drei Stunden nach IFN Injektion stark exprimiert wurden, und andere IRGs über einen Zeitraum von neun Stunden konstante oder auch dynamische Expressionsprofile aufwiesen. Auch fiel eine Dynamik in der Genexpression in den verschiedenen Organen auf, da viele IRGs schon drei Stunden nach IFN Injektion in der Milz, aber erst neun Stunden nach IFN Injektion in der Lunge stark exprimiert wurden. Dabei unterschieden sich zahlreiche nach IFN Injektion und NDV Infektion regulierten IRGs in Milz und Lunge, während andere IRGs in beiden Organen exprimiert wurden, was darauf schließen lässt, dass viele IRGs gewebespezifisch und andere eher global exprimiert werden.
Eine Vielzahl der nach IFN Applikation identifizierten IRGs konnte auch im Infektionsmodell mit lentogenem Newcastle Disease Virus bestätigt werden. Zudem gelang es, weitere „allgemeine IRGs“ zu identifizieren, was vermutlich auf die zusätzliche Expression von Typ II und Typ III IFN nach NDV Infektion zurückzuführen ist.
Zusammenfassend bleibt festzustellen, dass sich die durch IFN induzierten Gene beim Huhn zwischen den untersuchten Geweben und je nach Stimulus unterscheiden und neben den auch beim Säuger beschriebenen, eine Vielzahl an weiteren IRGs identifiziert werden konnte. Die erhaltene Übersicht von IRGs im Huhn kann nun als Grundlage genutzt werden, um potentielle antiviral wirksame IRGs auszuwählen und sie funktionell näher zu charakterisieren. Ein besseres Verständnis der IFN-Wirkungsweise beim Vogel könnte wesentlich zum Schutz von Huhn und Mensch vor gefährlichen Pandemien beitragen.Type I interferons (IFNs) are an indispensable part of the innate immune response and exhibit antiviral and immunomodulatory functions. Receptor binding of IFNs induces hundreds of so called IFN-regulated genes (IRGs), which mediate the main functions of IFNs. Applying different approaches, we were able to identify a comprehensive number of IRGs in the chicken for the first time. Therefore, we performed extensive comparative database analysis and transcriptome analysis of spleen and lung tissue after intravenous injection of recombinant chicken interferon alpha (rec ChIFN-α) as well as after infection with lentogenic Newcastle Disease Virus, which is a potent inductor of Type I IFN. After IFN injection, in addition to 30% of the “common IRGs”, which exist in mammals as well as in the chicken, about 1.900 “newly identified IRGs” were found, which were regulated in the chicken, but not in the mammalian IRG databases. A closer look at these IRGs revealed that both, “common“ and “newly identified IRGs”, were involved in immunrelevant biological processes and signalling cascades, like “complement and coagulation cascades”, “Toll-like receptor signalling pathway” and ”cytokine-cytokine receptor interaction”. Moreover, by network analysis it was possible to show that “common” and “newly identified IRGs” influence each other, which confirms the hypothesis of the identification of further IRGs in the chicken. We were able to show that chicken IRGs are expressed in different expression-profiles, with many IRGs expressed only three hours after IFN injection, while others showed either a constant expression over nine hours or a more dynamic expression-profile. Furthermore, this analysis revealed a dynamic organ specific IRG expression, as some IRGs were strongly induced after three hours in the spleen and but only after nine hours in the lung. In addition we were able to identify more globally expressed IRGs, which we found in spleen and lung tissue as well, and more tissue specific IRGs, which were expressed either in spleen or in lung tissue after IFN injection and/or NDV infection. Finally, a multitude of the identified chicken IRGs could be confirmed after infection with NDV. In this experiment we were able to confirm further “common IRGs”, probably mediated due to the expression of type II and type III IFNs after NDV infection. Altogether, we were able to show, that beside of many IRGs, which exist in mammals and in chickens, there are a multitude of additional IFN induced genes in the chicken. IRGs in chickens differ depending on stimulus and analysed tissue. The obtained overview of IRGs in chickens can provide a basis for further functional characterisation. A better understanding of IFN effector mechanism can help to protect chicken and humans from dangerous pandemic infections.
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Rodrigues, Ana Mara Lopes. "Interferon, virus vaccines and antiviral drugs." Thesis, University of St Andrews, 2008. http://hdl.handle.net/10023/428.
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The emergence of viruses with zoonotic potential, i.e. with the potential ability to cross species barriers to infect unnatural hosts, poses a huge threat to humans. It is therefore essential to develop new methodologies to rapidly and efficiently generate attenuated virus vaccine candidates to attempt to control the threat. Viruses need to be able to at least partially inhibit the host’s innate defence mechanism, known as the interferon (IFN) system, to replicate efficiently in vivo and establish a productive infection. It has been previously reported that viruses that have lost their ability to circumvent the host’s IFN response, or IFN-sensitive viruses, are promising candidates for live attenuated virus vaccines. Here we report on the development of a cell-based method to attempt to rapidly select IFN-sensitive viruses that can not block IFN signalling, from wild-type virus populations. Lentivirus vectors containing selection markers (HSV-tk – Herpes Simplex virus thymidine kinase gene and pac – puromycin resistance gene) under the control of a tight IFN-inducible promoter (the murine Mx1 promoter) were generated and used to specifically engineer HEp2 cell lines, termed Mx GIPSE and Mx TIPSE, for this purpose. The developed methodology relies on the engineered cell lines and a selection procedure using exogenous IFN-α and puromycin: if a cell is infected with IFN-resistant virus, it will die in the presence of IFN-α and puromycin because IFN signalling will be blocked, thereby blocking the activation of the Mx1 promoter and consequent expression of pac; if a cell is infected with an IFN-sensitive virus, it will survive in the presence of IFN-α and puromycin because the Mx1 promoter will become activated through the IFN signalling pathway, leading to the expression of pac. IFN-sensitive viruses can then be rescued from the surviving cells, and amplified using IFN-permissive cell lines expressing viral IFN antagonist proteins (proteins that block the host’s IFN response). When tested on PIV5 strains CPI- (an IFN-sensitive virus) and CPI+ (an IFN-resistant virus), the developed method allowed the survival and amplification of cells infected with CPI-, whilst cell death was observed for cells infected with CPI+. Whilst the developed methodology seems promising, further developments of the system are required. The possibilities of using the developed methodology in combination with other techniques, such as FACS sorting and immune selection, to rapidly select IFN-sensitive mutant viruses from wild-type and mutagenised virus populations are discussed. The potential to use Mx TIPSE cells to select IFN-resistant revertant viruses from IFN-sensitive virus populations is also discussed. In addition, a high throughput screening assay has been developed using the engineered Mx GIPSE and Mx TIPSE cell lines to search for compounds that block IFN signalling or that block the action of viral IFN antagonist proteins. Compounds that block IFN signalling would potentially be useful as anti-inflammatory drugs whilst compounds that block the action of viral IFN antagonist proteins would be valuable as antiviral drugs.
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Goncalves, Mario Nuno Penha. "Equine interferon-gamma and associated cytokines." Thesis, University of Glasgow, 2000. http://theses.gla.ac.uk/1064/.
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Cytokines are small proteins or glycoproteins that mediate cellular growth and differentiation and regulate immune responses. Upon encounter with antigen, CD4+ T cells are able to influence the character of the immune response elicited through the expression of distinct types of cytokines. Thl cytokines, especially IFN-γ but also TNF-β and IL-2, constitute one such pattern of expression, promoting cell mediated immune responses. In a broader sense, interleukin-12 and interleukin-18 can also be classified as type I cytokines in as much as they are able to shift the CD4+ cytokine expression pattern to a Thl phenotype and specifically stimulate IFN-γ production not only by T helper cells, but also by cytotoxic T cells and natural killer cells. The purpose of the present project was to develop equine Thl cytokines, making them available for dissecting the equine immune system, particularly in what concerns to defence mechanisms against infectious micro-organisms. Following the trend in human medicine, the cytokines produced will be useful for the development of new therapeuticals and prophylactics to be used in the control and prevention of infectious diseases of the horse. For this effect we have initiated studies on equine interferon-gamma and related cytokines and obtained the following results. Equine interferon-gamma was cloned and produced in a variety of heterologous protein-expression systems. The biological activity of recombinant equine interferon-gamma was assessed in vitro. Polyclonal serum preparations against equine interferon-gamma, obtained by immunization with recombinant protein, were recovered and characterised. Also described is the cloning of the interferon-gamma inducing cytokines equine interleukin-12 and equine interleukin-18. The potential use of the cloned equine cytokine genes as vaccine adjuvants was evaluated by DNA co-administration with plasmids encoding the equine influenza virus antigens haemagglutinin and nucleoprotein, followed by viral challenge.
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Ning, Shunbin. "Interferon Regulatory Factors and Autoimmune Diseases." Digital Commons @ East Tennessee State University, 2014. https://dc.etsu.edu/etsu-works/6542.
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Kong, Xiao-Fei. "Human genetic deficiencies of interferon responses." Paris 6, 2010. http://www.theses.fr/2010PA066195.
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Chen, Shu. "Studies on interferon (IFN) induction and isolation of IFN-inducing mutant viruses." Thesis, University of St Andrews, 2011. http://hdl.handle.net/10023/1678.
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The interferon (IFN) system is a powerful antiviral defense system. Host cell pattern recognition receptors (PRRs) recognise pathogen-associated molecule patterns (PAMPs) which when activated, lead to the transcription of the IFN-β gene. As a consequence IFN is secreted from the cell and activates the JAK-STAT pathway to up-regulate the transcription of IFN-stimulated genes (ISGs). The products of many ISGs inhibit viral replication and cell proliferation. Viruses encode IFN antagonists that dampen down the IFN response, making it less effective. However, within a virus population, there are always likely to be naturally occurring mutant viruses that have lost the ability to circumvent the host IFN response, and if isolated, these viruses would be unlikely to cause severe disease in the host and may therefore be developed as live attenuated virus vaccine candidates. To develop a methodology to rapidly isolate IFN-inducing mutant viruses, we generated an A549 reporter cell-line in which expression of GFP was driven by the IFN-β promoter. Using this cell-line, we show that the number of cells that became positive for GFP correlated with the amount of IFN secreted by the infected cells and the number of defective interfering (DI) particles within the virus preparations. However, we were unable to isolate IFN-inducing mutant viruses using the A549/pr(IFN-β).GFP cell-line(s). Possible reasons for this may be either that, in cells infected by IFN-inducing mutant viruses, an antiviral state was established independent of IFN that prevented virus replication in the reporter cells in which the IFN-β promoter was activated; or the viruses that activated the IFN-β promoter were DIs only which were not be able to replicate without non-defective helper viruses. A549/pr(IFN-β).GFP cells are also being used for high throughput assays to screen chemical libraries for compounds that block IFN induction. Such compounds may be potential candidates for anti-inflammatory drugs.
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O’Gorman, Maurice R. G. "Reduced in vitro IgG secretion following in vivo injection of interferon (wellferon R) in multiple sclerosis patients." Thesis, University of British Columbia, 1985. http://hdl.handle.net/2429/24876.
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An in vitro IgG secretion assay was developed to investigate the regulation of the humoral immune response in humans. Pokeweed mitogen (PWM), a plant lectin derived from Phytolacca americana stimulates human peripheral blood mononuclear cells (PBMNC) to divide and resting B-lymphocytes to differentiate into immunoglobulin secreting cells (ISC). This differentiation requires that both monocytes and T-lymphocytes be present in the culture system. The amount of IgG secreted by these differentiated B-lymphocytes in response to PWM appears to be the net result of a balance between the functional activity of the regulatory T-helper and T-suppressor cells. Alterations, qualitative or quantitative in any of these leukocyte subsets could conceivably alter the amount of IgG secreted by the B-lymphocyte subpopulation.
We have employed this assay to investigate the immune status in a group of chronic progressive multiple sclerosis (MS) patients and to assess the immunoregulatory effects of interferon (Wellferon R, INF) administered in vivo to this selected group. Their mononuclear cells (MNC) were studied in this PWM induced IgG secretion assay before INF treatment and again after 7 days of daily sub-cutaneous injections (5 X 10⁶ u/day). Twenty patients received the interferon (INF) preparation and eighteen received normal saline. The study was carried out in a double blind manner and the code was broken only after individual results had been calculated.Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
Graduate
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Kaldewey, Michaela. "Kombinationstherapie aus aktiver HBsAg-Vakzination und alpha-Interferon bei Interferon-Non-Respondern mit chronisch replikativer Hepatitis B." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=968538606.
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Ando, Mitsuru. "Development of liver-directed interferon-γ gene therapy system based on the spatiotemporal regulation of interferon-γ." 京都大学 (Kyoto University), 2013. http://hdl.handle.net/2433/175231.
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Vukotic, Ranka <1981>. "Serum anti-interferon alpha antibodies in chronic hepatitis C patients treated with pegylated interferon alpha containing therapy." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2015. http://amsdottorato.unibo.it/6910/1/Vukotic_Ranka_tesi.pdf.
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The development of anti-IFNα antibodies is an occurrence described in chronic hepatitis C patients during treatment with Interferonα/PEG-Interferonα. However, its relevance, especially in difficult-to treat patients, has not been defined. Methods: We retrospectively measured the serum levels of anti-IFNα antibodies (baseline and week 12) and IFNα levels (week 12) by ELISA in 76 previous non-responders, and in 14 naive patients treated with Pegylated-IFNα and Ribavirin. A group of 57 healthy donors (HD) was also assessed as control. Positivity to anti-IFNα antibodies was established on the values of HD. Results: Baseline anti-IFNα antibodies were detected in 15.5% of patients and in 7% of HD, with significantly higher concentrations in patients than HD (181.5±389.9 vs 95.9±143.0 ng mL−1, p=0.0023). All positive patients were IFNα-experienced. At week 12, the prevalence of positivity increased to 22.3 and 28.5% in experienced and naïve patients, respectively, and the levels of anti-IFNα antibodies did not differ between the two groups (391±792.3 vs 384.7±662.6 ng mL−1, respectively). IFNα concentrations were significantly lower in antibody-positive patients than in antibody-negatives (988.2±1402 vs 3462±830.8 pg mL−1, p≤0.0001) and the levels of antibodies and IFNα were inversely correlated (r=-0.405, p=0.0001). The antibody-positive population clustered in null responders (67%) and 19/21 patients (90%) did not achieve SVR. Conclusions: The development of anti-IFNα antibodies is a non-negligible occurrence in patients treated with PEG-IFNα, is stable over time, and has a relevant clinical impact when associated with low levels of circulating PEG-IFNα. It should be considered in patients undergoing treatments including PEG-IFNα.
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Vukotic, Ranka <1981>. "Serum anti-interferon alpha antibodies in chronic hepatitis C patients treated with pegylated interferon alpha containing therapy." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2015. http://amsdottorato.unibo.it/6910/.
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The development of anti-IFNα antibodies is an occurrence described in chronic hepatitis C patients during treatment with Interferonα/PEG-Interferonα. However, its relevance, especially in difficult-to treat patients, has not been defined. Methods: We retrospectively measured the serum levels of anti-IFNα antibodies (baseline and week 12) and IFNα levels (week 12) by ELISA in 76 previous non-responders, and in 14 naive patients treated with Pegylated-IFNα and Ribavirin. A group of 57 healthy donors (HD) was also assessed as control. Positivity to anti-IFNα antibodies was established on the values of HD. Results: Baseline anti-IFNα antibodies were detected in 15.5% of patients and in 7% of HD, with significantly higher concentrations in patients than HD (181.5±389.9 vs 95.9±143.0 ng mL−1, p=0.0023). All positive patients were IFNα-experienced. At week 12, the prevalence of positivity increased to 22.3 and 28.5% in experienced and naïve patients, respectively, and the levels of anti-IFNα antibodies did not differ between the two groups (391±792.3 vs 384.7±662.6 ng mL−1, respectively). IFNα concentrations were significantly lower in antibody-positive patients than in antibody-negatives (988.2±1402 vs 3462±830.8 pg mL−1, p≤0.0001) and the levels of antibodies and IFNα were inversely correlated (r=-0.405, p=0.0001). The antibody-positive population clustered in null responders (67%) and 19/21 patients (90%) did not achieve SVR. Conclusions: The development of anti-IFNα antibodies is a non-negligible occurrence in patients treated with PEG-IFNα, is stable over time, and has a relevant clinical impact when associated with low levels of circulating PEG-IFNα. It should be considered in patients undergoing treatments including PEG-IFNα.
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DEDONI, SIMONA. "Type I Interferon-induced neuronal damage: a study of the cellular and molecular mechanisms mediating interferon neurotoxicity." Doctoral thesis, Università degli Studi di Cagliari, 2011. http://hdl.handle.net/11584/266276.
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Type I interferons (IFNs) are known to cause neuropsychiatric side effects, including
cognitive and mood disturbances, through mechanisms still not completely defined.
To gain more information about type I IFN neurotoxicity, I investigated whether these
cytokines could act directly on neuronal cells and regulate intracellular signaling
pathways involved in cell death. In primary cultures of mouse cortical neurons acute
exposure to IFN-β induces a marked tyrosine phosphorylation of signal transducer
and activator of transcription (STAT) 1 and 3, whereas long-term exposure to the
cytokine increased the number of neuronal cells displaying an increased labeling for
cleaved caspase 3. In human SH-SY5Y neuroblastoma cells, used as a neuronal cell
model, type I IFNs rapidly stimulated the tyrosine phosphorylation of Janus kinase
(JAK) and STAT1, STAT3 and STAT5 and this response was antagonized by
blockade of type I IFN receptor. Prolonged exposure to IFN-β induced apoptotic cell
death accompanied by cytochrome C release, cleavage of caspase-9, -7, -3 and
poly-(ADP ribose) polymerase (PARP), DNA fragmentation and p38 mitogenactivated
protein kinase (p38 MAPK) phosphorylation. JAK inhibition reduced IFN-β-
stimulated Tyk2 and STAT1 phosphorylation, STAT1 transcriptional activity, induction
of double-stranded RNA-activated protein kinase (PKR), caspase cleavage and p38
MAPK phosphorylation. PKR induction was associated with enhanced PKR activity
and chemical inhibition of PKR reduced IFN-stimulated caspase activation.
Moreover, long-term IFN-β treatment led to down-regulation of phosphatidylinositol 3-
kinase (PI3K)/protein kinase B (Akt) signaling and IFN-β-induced apoptosis was
attenuated in cells expressing constitutively active Akt. The proapoptotic effect of
IFNs was markedly attenuated by pharmacological blockade of either glycogen
8
synthase kinase-3 (GSK-3) or p38 MAPK. In retinoic acid-differentiated SH-SY5Y
cells, treatment with IFN-β inhibited BDNF-induced regulation of Akt and GSK-3β,
activation of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2),
phosphorylation of tyrosine hydroxylase, and neuritogenesis. Thus, type I IFNs can
directly impair neuronal survival by regulating multiple mechanisms, including
activation of the canonical JAK-STAT signaling and the ancillary p38 MAPK pathway
and down-regulation of the PI3K/Akt and ERK1/2 signaling systems. The final
outcome of these molecular events is the activation of the apoptotic program and
impaired neuronal differentiation in response to neurotrophic stimuli. It is proposed
that these actions directed on neuronal cells may contribute to the neuropsychiatric
disturbances elicited by these cytokines.
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Stone, R. C., P. Du, D. Feng, K. Dhawan, Lars Rönnblom, Maija-Leena Eloranta, R. Donnelly, and B. J. Barnes. "RNA-Seq for Enrichment and Analysis of IRF5 Transcript Expression in SLE." Uppsala universitet, Reumatologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-194621.
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Polymorphisms in the interferon regulatory factor 5 (IRF5) gene have been consistently replicated and shown to confer risk for or protection from the development of systemic lupus erythematosus (SLE). IRF5 expression is significantly upregulated in SLE patients and upregulation associates with IRF5-SLE risk haplotypes. IRF5 alternative splicing has also been shown to be elevated in SLE patients. Given that human IRF5 exists as multiple alternatively spliced transcripts with distinct function(s), it is important to determine whether the IRF5 transcript profile expressed in healthy donor immune cells is different from that expressed in SLE patients. Moreover, it is not currently known whether an IRF5-SLE risk haplotype defines the profile of IRF5 transcripts expressed. Using standard molecular cloning techniques, we identified and isolated 14 new differentially spliced IRF5 transcript variants from purified monocytes of healthy donors and SLE patients to generate an IRF5 variant transcriptome. Next-generation sequencing was then used to perform in-depth and quantitative analysis of full-length IRF5 transcript expression in primary immune cells of SLE patients and healthy donors by next-generation sequencing. Evidence for additional alternatively spliced transcripts was obtained from de novo junction discovery. Data from these studies support the overall complexity of IRF5 alternative splicing in SLE. Results from next-generation sequencing correlated with cloning and gave similar abundance rankings in SLE patients thus supporting the use of this new technology for in-depth single gene transcript profiling. Results from this study provide the first proof that 1) SLE patients express an IRF5 transcript signature that is distinct from healthy donors, 2) an IRF5-SLE risk haplotype defines the top four most abundant IRF5 transcripts expressed in SLE patients, and 3) an IRF5 transcript signature enables clustering of SLE patients with the H2 risk haplotype.
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Meyerdierks, Anke. "Charakterisierung Interferon-gamma-induzierter Gene Interferon-induzierbares Protein 35, Nociceptin/Orphanin FQ und humanes Guanylat-bindendes Protein 3 /." [S.l.] : [s.n.], 1998. http://deposit.ddb.de/cgi-bin/dokserv?idn=956293263.
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Wissmann, Saskia. "Evaluation kognitiver Störungen bei Patienten mit chronischer Hepatitis C unter Therapie mit Interferon-[alpha] [Interferon-alpha] und Ribavirin." [S.l.] : [s.n.], 2001. http://deposit.ddb.de/cgi-bin/dokserv?idn=964429349.
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Migliorini, Adriana [Verfasser], and Hans-Joachim [Akademischer Betreuer] Anders. "Role of interferon-α and interferon-β in glomerular injury and repair / Adriana Migliorini. Betreuer: Hans-Joachim Anders." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2014. http://d-nb.info/1049891139/34.
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Klamp, Thorsten. "Identifizierung und Charakterisierung von VLIG-1, einer neuen Interferon-induzierten GTPase." [S.l. : s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=964404389.
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Barchet, Winfried. "Cellular origin and molecular expression mechanisms of virus-induced type I interferon in vivo." [S.l. : s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=964889234.
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Schneider-Fresenius, Christian. "Entwicklung eines neuen Interferon-[beta] mit erhöhter Löslichkeit und verbesserter Bioverfügbarkeit /." Stuttgart : Fraunhofer IRB Verl, 1999. http://www.gbv.de/dms/bs/toc/317370863.pdf.
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Dominguez, Palao Francisco. "Interferon induction by paramyxoviruses : investigations into specific RNA:protein interactions." Thesis, University of St Andrews, 2017. http://hdl.handle.net/10023/10750.
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RNA:protein interactions are central in many cellular processes, including activation of innate immune responses against microbial infection. Their study is essential to better understand the diverse biological events that occur within cells. However, isolation of RNA:protein complexes is often laborious and requires specialized techniques. This thesis is concerned with attempts to develop an improved purification protocol to isolate specific RNA:protein complexes. Taking advantage of the specific interaction of the Pseudomonas aeruginosa PP7 protein with its cognate RNA binding site, termed the PP7 recognition sequence (PRS), the aim was to identify cellular proteins involved in activating cell-signalling pathways, including the interferon-induction cascade, following viral infection with stocks of parainfluenza virus 5 (PIV5) rich in copyback defective interfering (DI) particles. Copyback DI genomes are powerful inducers of IFN and, here, I show they also activate the induction of IL-6, IL-8 and TNFα; cytokines that also have antiviral properties. Following the successful cloning of the PRS into a copyback DI genome, we investigated conditions for optimal in vitro capture of DI-PRS:protein complexes by PP7 on Dynabeads. When tested, the protocol led to the successful capture of ILF3 and PKR, two dsRNA binding proteins induced by IFN. We further developed a tap-tagging system to minimize the presence of non-specifically bound proteins to Dynabeads that may interfere with future mass spectrometry analysis. To isolate DI-PRS RNA:protein complexes from infected cells, attempts were made to rescue replicating DI-PRS genomes in the context of wild type PIV5. Similarly, efforts were made to isolate influenza A virus RNPs that contained the PRS in the neuraminidase (NA) gene from infected cells using the PP7-based protocol developed. However, for reasons discussed, unfortunately RNA:proteins complexes were not successfully purified from infected cells in either case.
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Smoak, Kathleen Azzam. "The Cardiac Interferon Response to Reovirus Infection." NCSU, 2003. http://www.lib.ncsu.edu/theses/available/etd-06232003-131502/.
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Viral myocarditis may be caused by a number of different viruses, and the mechanisms of pathogenicity can be both immune mediated and/or due to direct cytopathic effect. While extensive research has been done regarding immune-mediated mechanisms, the mechanisms of direct cytopathic effect remain largely unexplored. Reovirus induced murine myocarditis is not immune mediated, providing for an excellent disease model. Reovirus induction of, and sensitivity to, interferon-beta (IFN-ß) has previously been found to be an important determinant for protection against viral myocarditis. There are many interferon regulatory factors that can both regulate, and be regulated by, IFN-ß. In the first part of this dissertation, transient transfections of primary cardiac myocyte cultures (PCMCs) were used to investigate the role of interferon regulatory factor-1 (IRF-1) in regulation of IFN-ß. We found that while IRF-1 is downstream of the IFN response, it still plays an important protective role against viral myocarditis. In the next chapter, reovirus induction of Interferon Stimulated Genes (ISGs) was investigated in PCMCs and compared with a more generalized cell type, primary murine embryonic fibroblasts (PMEFs). Here we found that reovirus induction of ISGs is cell type-specific and interferon-mediated, yet levels of induction are discordant with viral induction of IFN. These results suggested that cell types that are prone to induction of IFN are resistant to induction of ISGs. In appendix I, reovirus induction of an Interferon Stimulated Response Element (ISRE) was investigated in the above mentioned cell types, providing insight into reovirus induction of ISGs and the cell type-specific response. In appendix II, the effect of IRF-1 on ISG induction was further examined by overexpressing IRF-1. These data indicated that IRF-1 could regulate ISGs and ISRE sequences, but that IFN may induce or activate a product that inhibits IRF-1 induction of these genes. In the final appendix, reovirus induction of the ISG, IRF-7, was investigated in PCMCs and PMEFs using real-time PCR. Here, we found that reovirus induction of IRF-7 is discordant with reovirus induction of IFN. Possible mechanisms of differential ISG induction are discussed in the summary of this dissertation to provide an overall picture of the cardiac IFN response to virus infection.
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Metz, Jesse de. "Pleiotropic responses to interferon-gamma in humans." [Amsterdam : Amsterdam : Thela-Thesis] ; Universiteit van Amsterdam [Host], 2000. http://dare.uva.nl/document/56816.
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Proefschrift Universiteit van Amsterdam.Ondertitel op omslag: Studies on metabolic, endocrine and immunological effects in healthy subjects and surgical patients. Met lit. opg. - Met samenvatting in het Nederlands.
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Xanthoudakis, Steven. "Regulation of the human interferon-b promoter." Thesis, McGill University, 1990. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=74353.
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Human type I interferons offer a relevant system to examine cell-specific inducible gene expression. Interferon genes are transcriptionally activated in a variety of cell types following induction by synthetic double-stranded RNA (poly I:C) and viruses. A transient expression system was developed which permits regulated expression of different IFN-CAT (chloramphenicol acetyltransferase) hybrid genes in human cells. Using this system in vivo competition assays identified positive and negative cellular factors interacting with the IFN-$ beta$ promoter. A factor that recognizes negative upstream regulatory sequences was also identified in uninduced myeloid cell extracts. Complementary studies demonstrated that transcription of the IFN-$ beta$ gene in vitro could be inhibited by a 44 bp synthetic oligonucleotide corresponding to the interferon regulatory element (IRE). This element is comprised of two genetically distinct positive regulatory domains, PRDI and PRDII, that are essential for maximal induction by virus or poly I:C. Binding and competition analysis showed that the PRDI element interacts with a factor(s) present in uninduced and virus-induced Hela extracts. The DNA-binding specificity of the PRDI factor(s) is characteristic of proteins recently shown to be involved in IFN-stimulated gene transcription. The PRDII domain is unrelated to PRDI, but shares 80% nucleotide homology with the NF-$ kappa$B binding site in the immunoglobulin kappa enhancer. PRDII was found to interact with an NF-$ kappa$B-like activity in both lymphoid and non-lymphoid cell extracts. An HIV-1 enhancer oligonucleotide containing two repeated $ kappa$B elements was interchangeable with PRDII in the gel retardation assay. UV-crosslinking analysis further revealed that several distinct inducible and constitutive proteins bind specifically to PRDII in different cell types, and suggests that multiple factors may interact with this element to regulate IFN-$ beta$ transcription. Taken togeth